Adverse skin reactions caused by chemical irritants are common among humans. Many of these irritants are constituents of cosmetic products while others are noxious industrial chemicals including organic solvents and caustic materials. In view of this wide spectrum of irritants, several physiologically injurious mechanisms have been postulated as underlying the adverse reactions. To deal with these possibilities, researchers have developed several classes of antiirritants.
According to Goldemberg, (In "Principles of Cosmetics for the Dermatologist", Phillip Frost and Stephen N. Horwitz, Eds., The C. V. Mosby Company, St. Louis, Mo. p.34; Goldemberg, R. M., 1979, J. Soc. Cosmet. Chem., 30:415) an antiirritant could be reacted with the irritant chemical to complex the irritant or change its nature so that it no longer irritates. Alternatively, the reactive skin sites can be blocked so that they no longer react with irritants. Additionally, a heavy layer of grease which is positioned between the skin and chemical irritants may also be used. Finally, the problem of irritation may be attenuated by extreme dilution of the irritant.
In general it is possible that chemical irritant injury of cells may be associated with the generation of toxic, free radicals. For example, when insulin secreting cells are exposed in vitro to solutions containing alloxan, hydroxyl radical is produced extracellularly with ensuing manifestations of plasma membrane damage. (Fischer, L. J. and Harmon, A. W. 1982, In "Pathology of Oxygen," Anne P. Auter. Ed. Academic Press. N.Y. p. 261). Paraquat, a pyrazine derivative which is easily reduced to a relatively stable free radical, is believed to augment the production of superoxide by chloroplasts and lung microsomes, and this is probably one reason for paraquats lethality in both plants and animals. (Hassan, H. M. and Fridovich, I., 1977, J. Bacteriol, 130:805; J. Bacteriol, 132:505). Also, carrageenan-induced and kaolin-induced inflammation in the rat has been suppressed by the use of the oxygen free radical scavenger, superoxide dismutase (Huber, W. and Saifer, M. G. 1977, In "Superoxide and Superoxide Dismutases", A. M. Michelson, J. M. McCord, and I. Fridovich, Eds. Academic Press, N.Y., 1977, p. 517; Oyanagui, Y., 1976, Biochem., Pharmacol, 25:1465).
It is known that biological reduction of molecular oxygen is accompanied by the production of reactive free-radical intermediates. The complete reduction of a molecule of oxygen to water requires four electrons, and in a sequential univalent process several intermediates are encountered. These are the superoxide anion-radical, hydrogen peroxide, and the hydroxyl radical, and such intermediates are too reactive to be well tolerated within living systems (Czapski, G. 1971, Annu. Rev. Phys. Chem., 22:171).
The superoxide anion radical, hydrogen peroxide and the hydroxyl radical which may be generated enzymatically or photochemically, are known to inactivate microorganisms, induce lipid peroxides, damage membranes and kill cells (Fridovich, I., 1982, In "Pathology of Oxygen," Anne P. Autor., Ed., Academic Press, Inc., New York.,p. 1). A primary defense against toxic oxygen radicals is provided by enzymes that catalytically scavenge the intermediates of oxygen reduction. For example, the superoxide anion radical may be eliminated by superoxide dismutases, which catalyze its conversion to hydrogen peroxide and oxygen.
There are indications that superoxide is not itself the species that causes injury to cells but may be the precursor of a more potent oxidant, the hydroxyl radical, the generation of which depends on the simultaneous presence of hydrogen peroxide. (Haber, R. and Weiss, 1934, J. Proc. Roy. Soc. London, Ser. A., 147:332). Thus, it seems that the greatest danger posed by superoxide is its interaction with hydrogen peroxide or with organic peroxides, which can generate a highly reactive entity like hydroxyl radical that can then attack essential cell components.
Several reports have appeared presenting data that the enzyme, superoxide dismutase (SOD), may function at the level of the skin. For example, two groups of researchers hav shown that systemic administration of SOD to rats will inhibit the reverse passive Arthus reaction in the skin (Petrone et al., 1980, Proc. Natl. Acad. Sci., 77:1159; Parellada, P. and Planas, J. M., 1978, Biochem. Pharm., 27:535). Further, treatment of facial lesions in patients with Crohn's disease with a topical application of liposomes containing superoxide dismutase was followed by marked improvement with a diminution of swelling (Michelson, A. M., 1982. In "Pathology of Oxygen", Anne P. Autor, Ed., Academic Press, N.Y., p. 277). Kalopissis et al. (U.S. Pat. No. 4,129,644 "Protecting Skin and Hair with Cosmetic Compositions Containing Superoxide Dismutase") claim that representative superoxide dismutase extracts of marine bacteria protect the keratinic structure of the skin of rats from the effects of intraperitoneally injected testosterone propionate. They additionally claim that topical application of a cream containing SOD would protect the skin from the harmful effects of ultra-violet rays produced by irradiation of human subjects with a Xenon, U.V. Solar Simulator. Other workers have shown that topical administration of a low molecular weight lipophilic copper coordination complex with superoxide dismutase-mimetic activity inhibits certain phorbol ester-induced biochemical and biological responses associated with carcinogenesis as well as the number of developing papillomas (Kensler, T. W., Bush, D. M., Kozumbo, W. J., 1983, Science, 221:75). Superoxide radical scavenging agents have also been used to protect rabbit cornea against alkali injury. (Nirakari et al., 1981, Arch. Ophthalmol., 99; 886). The unique avascularity of the cornea suggests that such oxygen radicals participate directly in the promotion of the corneal ulceration.
Until the present invention, however, agents for scavenging the intermediates of the biological reduction of oxygen have not been used to protect the skin from the deleterious action of diverse classes of chemical irritants. Moreover, there is no evidence indicating that the toxic dermal manifestations induced by a wide array of chemical irritants of the skin can be abrogated through the use of a single biological agent. Current knowledge of skin irritation requires use of divergent protective approaches as explained above. Finally, scavenger agents have not been suggested for use in the control of dermal inflammatory reactions including acne.
Accordingly, it is an object of the invention to provide a general method for prevention or alleviation of chemical irritation of the skin through the topical use of a single biological agent in combination with a suitable carrier or vehicle. Another object is the use of such a biological agent which scavenges free radical intermediates of biological oxidation-reduction reactions. It is a further object to use such an agent for the general control of dermal inflammation and acne. Other objects include the formulation of creme, gel, lotion and liquid preparations for the skin which will protect it from injury by diverse chemical irritants and will prevent or alleviate inflammation and acne.